The rapid recent development of recombinant antibody technology has produced approximately 30 antibodies that have been approved for human therapy and more than 270 that are currently in clinical development worldwide for a wide range of diseases. However, conventional antibody screening remains time- and labor-intensive and expensive. Traditionally, extracellular regions of target proteins have been used to screen antibodies. Consequently, most selected antibodies bind to cells, but are not functional antibodies with therapeutic potential. Due to recent advances in molecular biology and protein biochemistry, a large amount of information on protein domains and motifs that could link these structures to cell functions, is available. Use of a functional domain to screen recombinant antibodies may be an effective means of identifying functional antibodies and investigating underlying modes of action.
Tumor angiogenesis plays an important role in tumor progression. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) are key factors in angiogenesis, and targeting angiogenesis has become a promising strategy for cancer treatment. The anti-VEGF antibody bevacizumab has been used to treat patients with metastatic colorectal cancer, renal cell carcinoma, non-small-cell lung cancer, and malignant brain glioma. Cetuximab, an anti-EGFR antibody, may inhibit endothelial cell to cell contact and expression of angiogenic factors such as VEGF, interleukin-8, and basic fibroblast growth factor. However, due to the redundancy of tumor-secreted angiogenic factors, including placental growth factor, angiopoietin, basic fibroblast growth factor, and hepatocyte growth factor, these drugs generate a resistant phenotype in tumors (Kopetz S, et al., Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. Journal of Clinical Oncology. 28(3):453-9; Lucio-Eterovic A K, et al., Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy. Clinical Cancer Research. 2009; 15(14):4589-99).
The human VEGF antibody, bevacizumab, is now being used to treat patients with a variety of cancers. However, because the VEGF receptor (VEGFR) is also expressed on normal cells, its use is likely to be associated with adverse effects including hypertension, proteinuria, and gastrointestinal perforation. Adverse effects may also limit the therapeutic use of many antibodies against pro-angiogenic factors such as VEGFR-2 and angiopoietin-2. Consequently, identification of new cancer-specific targets for treating cancer patients by inhibition of angiogenesis is critical for developing therapeutic antibodies with fewer adverse effects.
In addition, bevacizumab and cetuximab are therapeutic antibodies that suppress angiogenesis by inhibiting interaction of soluble angiogenic growth factors and their receptors. However, long-term use of these drugs generates a resistant tumor phenotype due to redundancy of tumor cell-secreted pro-angiogenic growth factors. This may pose the greatest challenge to use of antibodies against soluble growth factors in patients requiring long-term therapy.
Clec14a is a type I transmembrane protein, the extracellular domain of which consists of a C-type lectin-like domain (CTLD), a series of epidermal growth factorlike domains, and a sushi-like domain. Several reports suggest a role by clec14a in tumor angiogenesis. Rho et al. reported that clec14a is endothelial cell-specific and may play a key role in cell to cell contact in angiogenesis (Rho S S, et al., Clec14a is specifically expressed in endothelial cells and mediates cell to cell adhesion. Biochemical & Biophysical Research Communications. 404(1):103-8). Mura et al. showed that clec14a is critical for regulating pro-angiogenic phenotypes associated with filopodium formation, cell migration, and endothelial tube formation; this group also identified clec14a as a tumor endothelial cell marker not expressed on the endothelium of normal tissues (Mura M, et al., Identification and angiogenic role of the novel tumor endothelial marker CLEC14A. Oncogene. 31(3):293-305).
Despite increasing interest in clec14a in recent years, its molecular mechanism has not been clearly identified. Studies on the functional portion or domain of cle14a which accounts for the angiogenesis must be conducted so as to excavate and develop clinically applicable antibodies. In this context, there is a pressing demand for a monoclonal antibody that specifically binds mouse and human clec14a and that is convertible into a humanized antibody or human antibody for preclinical and clinical study. Preferably, an antibody which is clinically applicable to the inhibition of tumor angiogenesis and thus to the treatment of cancer is needed. In addition, a novel part which suppresses tumor angiogenesis is needed to identify and thus further the suppression of angiogenesis and treatment of cancer.
The above information disclosed in this Background section is only for enhancement of understanding of the background of the present invention, and therefore it may contain information that does not form the prior art that is already known to a person of ordinary skill in the art.